Oleic acid induces endothelin-1 expression through activation of protein kinase C and NF-κB

The effect of acute treatment with non-esterified fatty acids (NEFA) on transmembrane signalling has been investigated in three different cell lines. In EGFR T17 cells, pretreatment with cis-unsaturated (oleic and palmitoleic acids) NEFA, but not with saturated or trans-unsaturated NEFA, inhibited the epidermal-growth-factor (EGF)-induced increases in cytosolic [Ca2+], membrane potential and Ins(1,4,5)P3 generation. The blocking effect was found to be time- and dose-dependent and rapidly reversible after washout. However, oleic acid treatment did not block either binding of 125I-EGF to its receptor or EGF-induced autophosphorylation of the EGF receptor. The mechanism of action of NEFA could not be attributed to protein kinase C activation, since (i) down-regulation of the enzyme by long-term treatment with phorbol esters did not prevent blockade by oleic acid, and (ii) the effects of acutely administered phorbol ester and oleic acid were additive. In this cell line, signalling at bradykinin and bombesin receptors was also impaired by oleic acid. In A431 cells, oleic acid also blocked signal transduction at the EGF and B2 bradykinin receptors. Finally, in PC12 cells, oleic acid blocked the Ca2+ influx mediated by the activation of B2 bradykinin receptors. In conclusion: (1) NEFA block signal transduction by interfering with receptor-phospholipase C or phospholipase C-substrate interaction without preventing ligand binding; (2) NEFA do not act by a protein kinase C-mediated mechanism; (3) the effect of NEFA is dependent on their configuration rather than hydrophobicity or chain length; (4) this effect is evident in several different cell lines and receptor systems.

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Flow-induced responses in cat isolated pulmonary arteries

Journal of Applied Physiology ◽

10.1152/jappl.1997.83.5.1617 ◽

1997 ◽

Vol 83 (5) ◽

pp. 1617-1622 ◽

Cited By ~ 16

Author(s):

Larissa A. Shimoda ◽

Nan A. Norins ◽

Jane A. Madden

Keyword(s):

Protein Kinase C ◽

Protein Kinase ◽

Pulmonary Arteries ◽

Transmural Pressure ◽

Induced Responses ◽

Synthesis Inhibitor ◽

Cell Deformability ◽

Endothelin 1 ◽

Kinase C ◽

Intracellular Ca

Shimoda, Larissa A., Nan A. Norins, and Jane A. Madden. Flow-induced responses in cat isolated pulmonary arteries. J. Appl. Physiol.83(5): 1617–1622, 1997.—Isolated, cannulated, endothelium-intact cat pulmonary arteries, averaging 692 ± 104 μm in diameter, were set at a transmural pressure of 10 mmHg and monitored with a video system. Intraluminal flow was increased in steps from 0 to 1.6 ml/min by using a syringe pump. An electronic system held pressure constant by changing outflow resistance. Flow-diameter curves were generated in physiological saline solution. At constant transmural pressure, the arteries constricted in response to increased intraluminal flow. Constriction was not affected by removing extracellular Ca2+ but was abolished after treatment with ryanodine to deplete intracellular Ca2+ stores, with the endothelin-1 synthesis inhibitor phosphoramidon, with the endothelin A-receptor antagonist BQ-123, with the protein kinase C inhibitor staurosporine, or with glutaraldehyde to reduce endothelial cell deformability. The results indicate that isolated pulmonary arteries can constrict in response to intraluminal flow and suggest that constriction is mediated by endothelin-1 and depends on intracellular Ca2+ release and protein kinase C activation.

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Palmitic Acid Increases Endothelin-1 Expression in Vascular Endothelial Cells through the Induction of Endoplasmic Reticulum Stress and Protein Kinase C Signaling

Cardiology ◽

10.1159/000490093 ◽

2018 ◽

Vol 140 (3) ◽

pp. 133-140 ◽

Cited By ~ 5

Author(s):

Juan Zhang ◽

Wen-Shu Zhao ◽

Xin Wang ◽

Lin Xu ◽

Xin-Chun Yang

Keyword(s):

Endothelial Cells ◽

Endoplasmic Reticulum ◽

Protein Kinase C ◽

Protein Kinase ◽

Palmitic Acid ◽

Er Stress ◽

Statistical Significance ◽

Saturated Fatty Acids ◽

Endothelin 1 ◽

Kinase C

Objective: We investigated the regulation of endothelin-1 (ET-1) expression in in vivo high-fat diet (HFD)-fed mice and in vitro cultured human aortic endothelial cells (HAECs). Methods: Male C57BL/6 mice were fed on standard chow, serum was prepared, and ET-1 levels were analyzed using an ELISA kit. Quantitative PCR was performed using iQ SYBR Green Supermix. Statistical significance was assessed using SPSS, with p < 0.05 considered significant. Results: The serum ET-1 content and endothelial expression of ET-1 mRNA were increased in the HFD-fed mice compared to the chow-fed control mice. Moreover, the mRNA expression of ET-1 was significantly increased in cultured HAECs in response to acute (< 24 h) and chronic (12–16 days) treatments with palmitic acid (PA), one of the most abundant saturated fatty acids in obesity. We found that the induction of ET-1 expression by PA was abolished by pretreating the cells with the endoplasmic reticulum (ER) stress inhibitor 4-phenylbutyric acid or the protein kinase C (PKC) inhibitor Gö 6850. Conclusion: Our findings demonstrate for the first time that PA increases ET-1 expression in endothelial cells through the induction of ER stress and the activation of PKC, providing novel mechanistic insights into the pathogenesis of obesity-associated hypertension and cardiovascular diseases.

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